Examples of known oxyiminoalkanoic acid derivatives are the intermediates used in the production of β-lactam compounds (Japanese Patent Application KOKAI No.49382/1983, 167576/1984, 77391/1987, 192387/1987, 47186/1991) and a compound having a leukotriene biosynthesis inhibiting effect (e.g., WO96/02507).
However, these compounds have not been reported to have hypoglycemic, hypolipidemic effects and retinoid-related receptor function adjuster activity yet.
On the other hand, oxime derivatives were reported as a prophylactic and/or therapeutic agent against hyperlipemia and hyperglycemia (e.g., Japanese Patent Application KOKAI No.48779/1997, 323929/1997), but these derivatives are not an oxyiminoalkanoic acid derivative.
Moreover, while a phenylalkanoyl acid derivative having a substituted hydroxyl group on its 4-position is reported (e.g. in WO97/31907, WO97/25042) as a peroxisome proliferator-activated receptor gamma (abbreviated occasionally as PPARγ in this specification) agonist which is one of retinoid-related receptor function adjusters, this derivative is not an oxyiminoalkanoic acid derivative.
The peroxisome proliferator-activated receptor gamma (PPARγ) is a member of an intranuclear hormone receptor superfamily, representatives of which are a steroid hormone receptor and a thyroidal hormone receptor, and induced to be expressed at a very early stage of the fat cell differentiation, and plays an important role as a master regulator in the fat cell differentiation. PPARγ is bound to a function adjuster to form a dinier with a retinoid X receptor (RXR), and is also bound to the responding site of a target gene in a nucleus, whereby regulating (activating) the transcription efficiency directly. Recently, a metabolite of prostaglandin D2, namely, 15-deoxy-Δ12,14prostaglandin J2, was proved to be an endogenous agonist of PPARγ, and some insulin sensitivity enhancing agent, such as a thiazolidinedione derivative, was proved to have a PPARγ agonistic activity, with its potency being in parallel with its blood sugar reducing effect and fat cell differentiation promoting effect [Cell, Vol. 83, page 803 (1995); The Journal of Biological Chemistry, Vol. 270, page 12953 (1995); Journal of Medicinal Chemistry, Vol. 39, page 655 (1996)]. More recently, it has been shown that: 1) PPARγ is expressed in a cultured, human fat sarcoma-derived cell, and its growth is terminated by addition of PPARγ agonist [Proceedings of the National Academy of Science of The United States of America, Vol. 94, page 237 (1997)], 2) a non-steroid antiinflammatory agent such as indomethacin and phenoprofen has a PPARγ agonistic activity [The Journal of Biological Chemistry, Vol. 272, page 3406 (1997)], 3) PPARγ is highly expressed in an activated macrophage, and the addition of its agonist serves to inhibit the transcription of a gene concerned in an inflammation [Nature, Vol. 391, p.79 (1998)], and 4) a PPARγ agonist inhibits the production of inflammatory cytokines (TNF α, IL-1 β, IL-6) by a monocyte [Nature, Vol. 391, page 82 (1998)].